Each year an estimated 1.5 million people sustain traumatic brain injury, presenting an enormous social and medical problem, with an economic burden exceeding $50 billion annually in the US. Head injury is one of the most important causes of acquired epilepsy; however, the mechanisms underlying post-traumatic epilepsy are not understood. Recently, we discovered that the GABAergic control of hippocampal pyramidal cells is subnetwork-specific (differential GABAergic inhibition exists for distinct pyramidal cell subpopulations) and temporally ordered (different interneuron subtypes fire in a particular temporal sequence during behaviorally relevant network oscillations). Here we propose to test the hypothesis that there is a significant disruption of the specialized, local GABAergic control o long-distance projecting excitatory pyramidal cells in post-traumatic epilepsy and that this compromised GABAergic inhibition constitutes a key mechanism underlying hyperexcitability and spontaneous seizures. The hypothesis will be tested in the controlled cortical impact model of traumatic brain injury during the chronic epilepsy phase, and the assessment will be carried out in the CA1 region of the mouse hippocampus with advanced in vitro and in vivo electrophysiological, immunocytochemical and optogenetic methods, complemented by data-driven, large-scale computational modeling approaches. The experiments of this proposal are designed to specifically target cellular-synaptic mechanisms underlying post-traumatic epilepsy and to test novel closed-loop optogenetic methods to stop chronic seizures in the post-traumatic brain. It is anticipated that defining the functional consequences of experimental post-traumatic epilepsy will aid in the future development of novel treatment strategies.